Introduction Hypoxia is defined as a reduction in the amount of oxygen (O2) available to any cell, tissue, or organism (Semenza, 2009). Research examined the effects of this reduction on endurance performance [see (Fulco et al., 1998) for review] and the benefits deriving from the exposure (and training) in hypoxia on the sea level endurance performance [see (Millet et al., 2010) for review]. However, endurance and ultra-endurance performances can also be performed in hypoxic environments. This is an intrinsic feature of those performances that either start from an altitude level and finish at a higher one or where the altitude profile changes during the race (e.g. uphill cycling time trial, running vertical kilometres, etc.). Accordingly, to date less is known about the determinants of performance where the severity of hypoxia changes during the trial (i.e. Progressive Hypoxia, PH). Therefore, the aim of this project was to investigate the effects of acute progressive hypoxia on the endurance performance and fatigue. A secondary aim was to determine the main physiological responses during these tasks in PH at different intensities of effort. Study I There are competitions like the mass start events (e.g. running and ski mountaineering vertical kilometres, cycling stages with uphill arrival, etc.) that take place in hypoxia, or even in progressive hypoxia, with the final high intensity effort at a higher altitude compared with the starting one. The aim of the study was to understand if a different hypoxic stimulus, during a submaximal cycling exercise (50% of relative Peak Power Output, PPO) impairs the high intensity performance of the final high intensity effort. After a maximal ramp test to obtain the PPO and baseline measurements of endurance performance (time to exhaustion, TTE) in a non-fatigued state (both in normoxia and in hypoxia) 8 subjects completed an 1-hour cycling protocol in normoxia (at 50% of PPO obtained in normoxia, N), constant hypoxia and progressive hypoxia (FiO2 = 13.4%, and FiO2 starting from 16.25 to 13.4%, at 50% of PPO obtained in hypoxia, Hcost and HH, respectively). TTE duration was reduced both after the N and Hcost session (-27.9% P=0.03 and -21.6% P=0.007, respectively) with no effect after HH. Higher oxygen saturation (SpO2) was observed during cycling exercise in N compared to the other two conditions. Hcost resulted in a lower SpO2 compared to HH, until the end of the 1-h bout, where Hcost and HH presented similar SpO2 due to similar altitude levels reached. Oxygen consumption was similar during the HH and Hcost condition, but Hcost is lower than in N (P=0.03). Rate of perceived exertion was similar in the three conditions. The primary finding of this study was that an impairment of ~25% in the endurance performance (tested through a TTE test and compared to a non-fatigued trial at baseline) was observed after both a normoxic (P=0.03) and a constant hypoxic (P=0.007) task; no effects after 1-h in HH. A possible explanation to the different effect of HH and Hcost on TTE performance can be related to the hypoxic dose (5.25 VS 3.75 kilometres/hour in Hcost VS HH, respectively). Study II There are competitions that take place in progressive hypoxia at a submaximal intensity throughout the entire duration with the final part of the race at a higher altitude compared to the starting one. The aim of this study was to investigate the effects of an 1-h exposure at different cycling submaximal intensities at progressive hypoxia on fatigue and endurance performance (tested through a Time To Exahustion, TTE). Peak power output (PPO) and baseline duration in a TTE were obtained in a non-fatigued state (both in normoxia and in hypoxia) in 11 subjects. Subsequently, in three separated days, they completed an 1-h protocol under the same progressively hypoxic stimulus (FiO2 starting from 16.25 to 13.4%, simulating an increase in altitude from 2000 to 3500 m) at different intensities: no effort (H_NoPO), 50% of the PPO in hypoxia (HH) and 50% of the PPO in normoxia (HN). Oxygen consumption, heart rate, blood lactate, cerebral blood flow and pulse oxygen saturation were monitored during each session. Neuromuscular fatigue was assessed pre and post the 1-h intervention as well as after the subsequent TTE. We observed a reduced duration of TTE only after 1-h HN, when compared to baseline and H_NoPO (-37.2% P<0.001 and -30.8% P=0.016). One of the reason of this impairment in performance can be the higher blood lactate accumulation and the higher RPE during 1-h HN. The general reduction in SpO2 during the three interventions may be one of the causes of the reduction in voluntary activation, as an index of central fatigue, even though cerebral blood flow increased with time without any differences between conditions. The novelty of this study was to investigate the acute effects on performance and fatigue at different submaximal intensities when athletes are exposed to a progressively increased hypoxia. The main finding was that the endurance performance (assessed by means of TTE, that can be considered as the final high intensity effort at a higher altitude compared with the starting one) was only compromised after 1-h of cycling at 50% of the absolute peak power output obtained in normoxia. Therefore, it can be a good practice to test athletes that need to perform at altitude, in simulated condition. General conclusion Progressive hypoxia is a condition encountered during several endurance and ultra endurance performances. The understanding of the effects driven by a PH exposure at different intensities on a subsequent endurance performance can be useful for coaches and athletes that need to plan and pace their efforts in similar environments. We need to be conscious that in altitude, and especially in PH, the threshold between choosing the correct intensity of an effort and the intensity that can results in a subsequent impairment during an endurance performance (TTE) is really thin. Therefore, it can be a good practice to test athletes that need to perform at altitude, in a similar condition. Finally, we can conclude that a small step forward in the understanding of efforts during a progressive hypoxic stimulus has been provided. More work is needed, and the next step could be to study PH in field performances.